Did AIM-HIGH Start Too Low?

Serum levels of high-density lipoprotein cholesterol (HDL-C) are a widely validated predictor of risk for cardiovascular (CV) disease in both men and women.1,2 Low levels of HDL-C are associated with increased risk for CV events, including stroke, nonfatal myocardial infarction (MI) and death, while high levels portend lower risk for these clinical endpoints. A number of meta-analyses have suggested that use of statin therapy to elevate HDL-C contributes to the capacity of the statin drugs to reduce risk both for coronary artery disease (CAD) progression and for acute CV events.3-5 Important post hoc analyses from the Air Force/Texas Coronary Atherosclerosis Prevention Study6 and Bezafibrate Infarction Prevention Study7 show that even small increases in HDL-C on statin and fibrate therapy contribute to risk reduction. In patients with established CAD or who require percutaneous coronary interventions, low HDL-C is associated with poorer long-term outcomes.

 

HDL-C and Atherogenicity

The contention that HDL particles are antiatherogenic is certainly plausible from a biological standpoint. The most important antiatherogenic function attributable to HDL particles is likely their ability to engage in reverse cholesterol transport (RCT),8 the process by which HDL particles interact with lipid-laden macrophages in the subendothelial space, promote mobilization and externalization of cholesterol, and transport cholesterol back to the liver.

A recent elegant clinical investigation demonstrated that HDL-dependent efflux capacity correlates with risk for CAD in humans.9 HDL particles are important transporters of micro-messenger RNA that regulate cellular function and also carry a large variety of proteins, apolipoproteins, sphingolipids, ribonucleic acids and enzymes that determine HDL particle function.10

In terms of cardiac protection and other beneficial health effects, HDL particles can reduce lipid oxidation, reverse endothelial dysfunction, influence platelet activation, decrease inflammation and participate in systemic insulin sensitization.11,12 HDL is clearly vastly distinct from such atherogenic lipoproteins as low-density or very low-density lipoproteins.

Niacin and HDL-C

Niacin (or nicotinic acid) is the best drug currently available for raising serum levels of HDL-C. Niacin binds to cell surface receptors present in a number of tissues and exerts complex effects on lipid and lipoprotein production and clearance.13 As monotherapy, niacin reduced the risk of MI and ischemic stroke by 26% and 24%, respectively, in studies of patients with CAD.14

In small studies, the combination of niacin and a statin appeared to provide outsized levels of reduction in risk for CV events.15,16 In the HDL Atherosclerosis Treatment Study (HATS), the use of high-dose niacin in combination with simvastatin compared with placebo yielded an 89% relative risk reduction for CV events and induced modest regression of atherosclerotic plaque based on quantitative coronary angiography in patients with CAD.16 At baseline, patients treated with combination therapy had a low-density lipoprotein cholesterol (LDL-C) level of 124 mg/dL, HDL-C of 34 mg/dL, and triglycerides of 158 mg/dL. Due to the small patient population of the HATS trial, which randomized approximately 40 patients to each treatment arm, a larger study was needed to validate or refute these findings.

Niacin in the AIM-HIGH Study

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial was designed to compare the efficacy of statin monotherapy with statinniacin combination therapy in patients with established CAD.17 The trial enrolled 3,414 participants in the United States and Canada with a history of cardiovascular disease and randomized subjects to treatment with either simvastatin alone or in combination with ezetimibe adjuvant therapy or simvastatin/ezetimibe with extended release niacin therapy of 1,500 to 2,000 mg daily. The target LDL-C before randomization was 40 to 80 mg/dL. Baseline characteristics appear in the Table.

Table

Click here for larger version of Table.

The primary endpoint for AIM-HIGH was a composite defined as time to first occurrence of any of the following:

  • Coronary heart disease death
  • Nonfatal MI
  • Ischemic stroke
  • Hospitalization for acute coronary syndrome
  • Symptom-driven coronary or cerebral revascularization

Background therapy for all risk factors (blood pressure, blood glucose) was rigorous and met the goals set forth in guidelines for high-risk patients. The addition of niacin to half of the patients did provide incremental HDL-C elevation and triglyceride reduction. However, the National Heart, Lung, and Blood Institute (the sponsor of the study) halted the trial prematurely because continuing was deemed futile after interim analyses showed no significant difference in adverse outcomes between the 2 groups (249 primary outcome events [15%] in the simvastatin arm and 262 [15%] in the simvastatin/niacin arm; hazard ratio 1.053, 97.5% CI: 0.885–1.252; P =0.561).18 Moreover, investigators observed an excess hazard for ischemic stroke (28 vs. 12) that was numerically, though not statistically, significant in the group receiving niacin. No other studies have suggested that niacin somehow potentiates risk for ischemic stroke, and certainly concern has been voiced that AIM-HIGH may have been terminated prematurely despite the rigorous statistical analysis.

The HDL Hypothesis

So, should physicians stop using niacin to treat low serum levels of HDL-C? Does AIM-HIGH refute the HDL hypothesis? Do the results of AIM-HIGH refute the findings of other positive studies with niacin?

 

I believe the answer to all of these questions is “no.” The patients in AIM-HIGH represent a small fraction of those with CAD typically encountered in clinical practice. For the most part, these patients were very aggressively treated, had been on ongoing lipid-lowering therapy, and their atherogenic lipoprotein burden (LDL-C = 71 mg/dL and non-HDL-C 106 = mg/dL) was quite low, closely approximating the National Cholesterol Education Program targets for patients at high risk.19 Patients’ other risk factors were aggressively treated and controlled.

An appropriate interpretation of these data is that the patient population defined by AIM-HIGH did not benefit from adjuvant niacin therapy, and at least during the 2.5-year average follow-up period, raising HDL-C provided no incremental benefit, probably because these patients received such intensive, comprehensive, long-term risk factor management.

The AIM-HIGH data do not refute the HDL hypothesis or the findings of the Familial Atherosclerosis Treatment Study,20 HATS16 or the Armed Forces Regression Study.21 These studies all used different approaches to lipid modification with combinations of drugs that included niacin and different inclusion and exclusion criteria and baseline lipid profiles. Niacin should still be used to help patients attain their risk stratified NCEP LDL-C and non-HDL-C goals. If high-risk patients have attained these goals with other drugs despite having a low baseline HDL-C, then, consistent with AIM-HIGH, niacin adjuvant therapy provides no further incremental benefit.

A study larger than AIM-HIGH known as the Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study is still underway and includes approximately 20,000 patients from the United Kingdom, China and various Scandinavian countries. HPS2-THRIVE will provide much more needed information about adjuvant therapy with niacin in a broader spectrum of patients on statin therapy. Subsequent to the announcement that AIM-HIGH was being terminated, an interim analysis of the HPS2-THRIVE cohort did not suggest futility, and the trial remains ongoing.22

 

The capacity of HDL particles to induce coronary atherosclerotic disease regression has been shown in a number of studies that used HDL infusion therapy.23,24 Much insight into the role of HDL elevation in preventing and managing CAD will be provided by studies using the cholesterol ester transfer protein inhibitors, such as anacetrapib and dalcetrapib. It is far too early to abandon efforts to raise HDL in order to reduce residual risk in patients on statin therapy.

References

1. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease–the Framingham Heart Study. Can J Cardiol. 1988;4(suppl A):5A-10A.

2. Assmann G, Cullen P, Schulte H. The Münster heart study (procam). Results of follow-up at 8 years. Eur Heart J. 1998;19(suppl A):A2-A11.

3. Ballantyne CM, Raichlen JS, Nicholls SJ, Erbel R, Tardif JC, Brener SJ, et al. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: A study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation. 2008;117:2458-2466.

4. Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499-508.

5. Brown B, Zhao X, Cheung M. Should both HDL-C and LDL-C be targets for lipid therapy? A review of current evidence. J Clin Lipidol. 2007;1:88-94.

6. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615-1622.
7. Goldenberg I, Goldbourt U, Boyko V, Behar S, Reicher-Reiss H. Bevacizumab Infarction Prevention trial study group. Relation between on-treatment increments in serum high-density lipoprotein cholesterol levels and cardiac mortality in patients with coronary heart disease (from the Bezafibrate Infarction Prevention trial). Am J Cardiol. 2006;97:466-471.

8. Toth PP. Reverse cholesterol transport: High-density lipoprotein's magnificent mile. Curr Atheroscler Rep. 2003;5:386-393.

9. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127-135.

10. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117:746-756.

11. Toth PP. Activation of intracellular signaling systems by high-density lipoproteins. J Clin Lipidol. 2010;4:376-381.

12. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13:423-433.

13. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S. PUMA-G and HM-74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 2003;9:352-355.

14. [no authors listed]. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360-381.

15. Brunzell JD, Hokanson JE. Low-density and high-density lipoprotein subspecies and risk for premature coronary artery disease. Am J Med. 1999;107:16S-18S.

16. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.

17. AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: Baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/High triglycerides: Impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. 2011;161:538-543.

18. National Institutes of Health. NIH stops clinical trial on combination cholesterol treatment [press release]. http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2792. Accessed November 30, 2011.

19. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

20. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin J-T, Kaplan C, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein b. New Engl J Med. 1990;323:1289-1298.

21. Whitney EJ, Krasuski RA, Personius BE, Michalek JE, Maranian AM, Kolasa MW, et al. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: Effects on progression of coronary heart disease and clinical events. Ann Intern Med. 2005;142:95-104.

22. Clinical Trial Service Unit and Epidemiological Studies Unit, Oxford. HPS2- THRIVE press release: Launch of major international study to test new drug combination to cut cardiovascular disease. http://www.ctsu/ox.ac.uk/pressreleases/2006-05-31/hps2-thrive-press-release. Accessed November 30, 2011.

23. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant apoa-i milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA. 2003;290:2292-2300.

24. Tardif JC, Gregoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: A randomized controlled trial. JAMA. 2007;297:1675-1682.

Serum levels of high-density lipoprotein cholesterol (HDL-C) are a widely validated predictor of risk for cardiovascular (CV) disease in both men and women.1,2 Low levels of HDL-C are associated with increased risk for CV events, including stroke, nonfatal myocardial infarction (MI) and death, while high levels portend lower risk for these clinical endpoints. A number of meta-analyses have suggested that use of statin therapy to elevate HDL-C contributes to the capacity of the statin drugs to reduce risk both for coronary artery disease (CAD) progression and for acute CV events.3-5 Important post hoc analyses from the Air Force/Texas Coronary Atherosclerosis Prevention Study6 and Bezafibrate Infarction Prevention Study7 show that even small increases in HDL-C on statin and fibrate therapy contribute to risk reduction. In patients with established CAD or who require percutaneous coronary interventions, low HDL-C is associated with poorer long-term outcomes.

 

HDL-C and Atherogenicity

The contention that HDL particles are antiatherogenic is certainly plausible from a biological standpoint. The most important antiatherogenic function attributable to HDL particles is likely their ability to engage in reverse cholesterol transport (RCT),8 the process by which HDL particles interact with lipid-laden macrophages in the subendothelial space, promote mobilization and externalization of cholesterol, and transport cholesterol back to the liver.

A recent elegant clinical investigation demonstrated that HDL-dependent efflux capacity correlates with risk for CAD in humans.9 HDL particles are important transporters of micro-messenger RNA that regulate cellular function and also carry a large variety of proteins, apolipoproteins, sphingolipids, ribonucleic acids and enzymes that determine HDL particle function.10

In terms of cardiac protection and other beneficial health effects, HDL particles can reduce lipid oxidation, reverse endothelial dysfunction, influence platelet activation, decrease inflammation and participate in systemic insulin sensitization.11,12 HDL is clearly vastly distinct from such atherogenic lipoproteins as low-density or very low-density lipoproteins.

Niacin and HDL-C

Niacin (or nicotinic acid) is the best drug currently available for raising serum levels of HDL-C. Niacin binds to cell surface receptors present in a number of tissues and exerts complex effects on lipid and lipoprotein production and clearance.13 As monotherapy, niacin reduced the risk of MI and ischemic stroke by 26% and 24%, respectively, in studies of patients with CAD.14

In small studies, the combination of niacin and a statin appeared to provide outsized levels of reduction in risk for CV events.15,16 In the HDL Atherosclerosis Treatment Study (HATS), the use of high-dose niacin in combination with simvastatin compared with placebo yielded an 89% relative risk reduction for CV events and induced modest regression of atherosclerotic plaque based on quantitative coronary angiography in patients with CAD.16 At baseline, patients treated with combination therapy had a low-density lipoprotein cholesterol (LDL-C) level of 124 mg/dL, HDL-C of 34 mg/dL, and triglycerides of 158 mg/dL. Due to the small patient population of the HATS trial, which randomized approximately 40 patients to each treatment arm, a larger study was needed to validate or refute these findings.

Niacin in the AIM-HIGH Study

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial was designed to compare the efficacy of statin monotherapy with statinniacin combination therapy in patients with established CAD.17 The trial enrolled 3,414 participants in the United States and Canada with a history of cardiovascular disease and randomized subjects to treatment with either simvastatin alone or in combination with ezetimibe adjuvant therapy or simvastatin/ezetimibe with extended release niacin therapy of 1,500 to 2,000 mg daily. The target LDL-C before randomization was 40 to 80 mg/dL. Baseline characteristics appear in the Table.

Table

Click here for larger version of Table.

The primary endpoint for AIM-HIGH was a composite defined as time to first occurrence of any of the following:

  • Coronary heart disease death
  • Nonfatal MI
  • Ischemic stroke
  • Hospitalization for acute coronary syndrome
  • Symptom-driven coronary or cerebral revascularization

Background therapy for all risk factors (blood pressure, blood glucose) was rigorous and met the goals set forth in guidelines for high-risk patients. The addition of niacin to half of the patients did provide incremental HDL-C elevation and triglyceride reduction. However, the National Heart, Lung, and Blood Institute (the sponsor of the study) halted the trial prematurely because continuing was deemed futile after interim analyses showed no significant difference in adverse outcomes between the 2 groups (249 primary outcome events [15%] in the simvastatin arm and 262 [15%] in the simvastatin/niacin arm; hazard ratio 1.053, 97.5% CI: 0.885–1.252; P =0.561).18 Moreover, investigators observed an excess hazard for ischemic stroke (28 vs. 12) that was numerically, though not statistically, significant in the group receiving niacin. No other studies have suggested that niacin somehow potentiates risk for ischemic stroke, and certainly concern has been voiced that AIM-HIGH may have been terminated prematurely despite the rigorous statistical analysis.

The HDL Hypothesis

So, should physicians stop using niacin to treat low serum levels of HDL-C? Does AIM-HIGH refute the HDL hypothesis? Do the results of AIM-HIGH refute the findings of other positive studies with niacin?

 

I believe the answer to all of these questions is “no.” The patients in AIM-HIGH represent a small fraction of those with CAD typically encountered in clinical practice. For the most part, these patients were very aggressively treated, had been on ongoing lipid-lowering therapy, and their atherogenic lipoprotein burden (LDL-C = 71 mg/dL and non-HDL-C 106 = mg/dL) was quite low, closely approximating the National Cholesterol Education Program targets for patients at high risk.19 Patients’ other risk factors were aggressively treated and controlled.

An appropriate interpretation of these data is that the patient population defined by AIM-HIGH did not benefit from adjuvant niacin therapy, and at least during the 2.5-year average follow-up period, raising HDL-C provided no incremental benefit, probably because these patients received such intensive, comprehensive, long-term risk factor management.

The AIM-HIGH data do not refute the HDL hypothesis or the findings of the Familial Atherosclerosis Treatment Study,20 HATS16 or the Armed Forces Regression Study.21 These studies all used different approaches to lipid modification with combinations of drugs that included niacin and different inclusion and exclusion criteria and baseline lipid profiles. Niacin should still be used to help patients attain their risk stratified NCEP LDL-C and non-HDL-C goals. If high-risk patients have attained these goals with other drugs despite having a low baseline HDL-C, then, consistent with AIM-HIGH, niacin adjuvant therapy provides no further incremental benefit.

A study larger than AIM-HIGH known as the Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study is still underway and includes approximately 20,000 patients from the United Kingdom, China and various Scandinavian countries. HPS2-THRIVE will provide much more needed information about adjuvant therapy with niacin in a broader spectrum of patients on statin therapy. Subsequent to the announcement that AIM-HIGH was being terminated, an interim analysis of the HPS2-THRIVE cohort did not suggest futility, and the trial remains ongoing.22

 

The capacity of HDL particles to induce coronary atherosclerotic disease regression has been shown in a number of studies that used HDL infusion therapy.23,24 Much insight into the role of HDL elevation in preventing and managing CAD will be provided by studies using the cholesterol ester transfer protein inhibitors, such as anacetrapib and dalcetrapib. It is far too early to abandon efforts to raise HDL in order to reduce residual risk in patients on statin therapy.

References

1. Castelli WP. Cholesterol and lipids in the risk of coronary artery disease–the Framingham Heart Study. Can J Cardiol. 1988;4(suppl A):5A-10A.

2. Assmann G, Cullen P, Schulte H. The Münster heart study (procam). Results of follow-up at 8 years. Eur Heart J. 1998;19(suppl A):A2-A11.

3. Ballantyne CM, Raichlen JS, Nicholls SJ, Erbel R, Tardif JC, Brener SJ, et al. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: A study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation. 2008;117:2458-2466.

4. Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, et al. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007;297:499-508.

5. Brown B, Zhao X, Cheung M. Should both HDL-C and LDL-C be targets for lipid therapy? A review of current evidence. J Clin Lipidol. 2007;1:88-94.

6. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615-1622.
7. Goldenberg I, Goldbourt U, Boyko V, Behar S, Reicher-Reiss H. Bevacizumab Infarction Prevention trial study group. Relation between on-treatment increments in serum high-density lipoprotein cholesterol levels and cardiac mortality in patients with coronary heart disease (from the Bezafibrate Infarction Prevention trial). Am J Cardiol. 2006;97:466-471.

8. Toth PP. Reverse cholesterol transport: High-density lipoprotein's magnificent mile. Curr Atheroscler Rep. 2003;5:386-393.

9. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127-135.

10. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117:746-756.

11. Toth PP. Activation of intracellular signaling systems by high-density lipoproteins. J Clin Lipidol. 2010;4:376-381.

12. Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13:423-433.

13. Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S. PUMA-G and HM-74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med. 2003;9:352-355.

14. [no authors listed]. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231:360-381.

15. Brunzell JD, Hokanson JE. Low-density and high-density lipoprotein subspecies and risk for premature coronary artery disease. Am J Med. 1999;107:16S-18S.

16. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592.

17. AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: Baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/High triglycerides: Impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. 2011;161:538-543.

18. National Institutes of Health. NIH stops clinical trial on combination cholesterol treatment [press release]. http://public.nhlbi.nih.gov/newsroom/home/GetPressRelease.aspx?id=2792. Accessed November 30, 2011.

19. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.

20. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin J-T, Kaplan C, et al. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein b. New Engl J Med. 1990;323:1289-1298.

21. Whitney EJ, Krasuski RA, Personius BE, Michalek JE, Maranian AM, Kolasa MW, et al. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: Effects on progression of coronary heart disease and clinical events. Ann Intern Med. 2005;142:95-104.

22. Clinical Trial Service Unit and Epidemiological Studies Unit, Oxford. HPS2- THRIVE press release: Launch of major international study to test new drug combination to cut cardiovascular disease. http://www.ctsu/ox.ac.uk/pressreleases/2006-05-31/hps2-thrive-press-release. Accessed November 30, 2011.

23. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant apoa-i milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA. 2003;290:2292-2300.

24. Tardif JC, Gregoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: A randomized controlled trial. JAMA. 2007;297:1675-1682.